Suppressors of cytokine signalling: SOCS

Abstract

The mechanism of positive regulation of cytokine signalling pathways has been well investigated, whereas our knowledge of negative regulation is relatively sparse. Here we review recent literature on important negative regulators: the family of suppressors of cytokine signalling, SOCS, consisting of eight members (SOCS-1 to SOCS-7 and CIS) all sharing a central SH2 domain and a C-terminal SOCS box. Expression of CIS, SOCS-1, SOCS-2 and SOCS-3 is induced by various cytokines, and overexpression studies in various cell lines have demonstrated their inhibitory roles. These family members have been implicated in the negative regulation of several pathways, particularly the JAK/STAT pathway, and since this signalling pathway is responsible for their induction, they form part of a classical negative feedback circuit. To date, at least three different modulating mechanisms have been demonstrated: through the SH2 domain they bind to phosphotyrosines on the target protein, leading to inhibition of signal transduction by N-terminal inactivation of JAK, by blocking access of STAT to the receptor sites, or by SOCS box-targeting bound proteins to proteasomal degradation. In gene modification studies in mice, it has been demonstrated that SOCS-1 plays an important role in IFNgamma-regulation and T-cell differentiation, while SOCS-2 seems necessary for normal growth regulation. SOCS-3(-/-) mice die during embryogenesis for a reason still not fully understood, but insufficient control of fetal erythropoiesis or defects in placental development may be involved. The physiological role for the other family members, as well as their molecular regulation mechanisms, remain to be revealed.

SOCS2: inhibitor of JAK2V617F-mediated signal transduction

“…25 In polycythemia vera, low-level expression of SOCS2 in insulin-like growth factor-I-treated BFU-E colonies contributes to IGF-I hypersensitivity and to erythroid overgrowth. 26 These observations suggest that the oncogenic effect of the JAK2V617F mutation may be amplified by downregulation of SOCS2.…”

Decreased infarct size after focal cerebral ischemia in mice chronically infected with Toxoplasma gondii

“…In fact, the effect of infection on ischemic damage may largely depend on the regulation of reactive oxygen species by pro-inflammatory and anti-inflammatory cytokines as well as by the main antioxidant state regulators, namely superoxide dismutase (SOD) (Guegan et al, 1998;Murakami et al, 1998), glutathione (GSH) (Nicholls and Budd, 2000;Schulz et al, 2000;Droge, 2002), uncoupling protein-2 (UCP2) (Arsenijevic et al, 2000b;Mattiasson et al, 2003) and nerve growth factor (NGF) (Brodie, 1996;Guegan et al, 1999;Villoslada et al, 2000). In addition, the newly described suppressor of cytokine signaling (SOCS) proteins are induced in peripheral and central models of inflammation (Lebel et al, 2000;Bates et al, 2001;Larsen and Ropke, 2002;Wang and Campbell, 2002;Huang et al, 2003;Park et al, 2003;Jo et al, 2005). SOCS possibly interact with cellular redox determinants (Park et al, 2003) and transgenic SOCS expression has been shown to inhibit inflammation and apoptosis following lipopolysaccharide (LPS) injection (Jo et al, 2005).…”

A Suppressor of Cytokine Signaling 1 Antagonist Enhances Antigen-Presenting Capacity and Tumor Cell Antigen-Specific Cytotoxic T Lymphocyte Responses by Human Monocyte-Derived Dendritic Cells

“…There are four major ways that SOCS proteins inhibit cytokine signaling (51), (i) by blocking STAT recruitment to the cytokine receptor, (ii) by targeting the receptor for degradation by the proteasome, (iii) by binding to JAKs and directly inhibiting their kinase activity, and (iv) by targeting JAKs for degradation by the proteasome. The SOCS family consists of eight members (SOCS1 to SOCS7 and CIS) that contain a conserved SOCS box, a central SH2 domain, and an N terminus of variable length and organization (52)(53)(54). Two of the family members, SOCS1 and SOCS3, contain a kinase inhibitory region (KIR) that serves as a pseudosubstrate for JAKs, blocking JAK kinase activity even in the absence of the SOCS box (55).…”